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Cancer research: from folate antagonism to molecular targets

Joseph R Bertino1

  • 1Department of Molecular Therapeutics, The Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA. bertinoj@umdnj.edu

Best Practice & Research. Clinical Haematology
|December 5, 2009
PubMed

Insights

Aminopterin and methotrexate were pioneering drugs in cancer treatment. Methotrexate remains a crucial antifolate therapy for malignancies, with ongoing research into drug resistance mechanisms and new therapeutic agents.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Antifolates like aminopterin and methotrexate revolutionized cancer therapy.
  • Methotrexate (MTX) achieved the first curative treatment for solid tumors (choriocarcinoma).
  • Over 50 years later, MTX remains a cornerstone in cancer treatment and research.

Purpose of the Study:

  • To review the historical significance and ongoing relevance of antifolates in oncology.
  • To explore the mechanisms of action and resistance related to dihydrofolate reductase (DHFR).
  • To highlight advancements in antifolate-based therapies and drug resistance strategies.

Main Methods:

  • Review of historical clinical data and pharmacological studies.
  • Analysis of research on dihydrofolate reductase (DHFR) and thymidylate synthase (TS) inhibition.
  • Examination of studies on drug resistance mechanisms, including gene amplification and mutations.
  • Investigation of novel therapeutic strategies, including gene therapy approaches.

Main Results:

  • Aminopterin and MTX demonstrated early successes in treating acute lymphocytic leukemia and choriocarcinoma.
  • DHFR is a key target, and its gene amplification/mutations contribute to antifolate resistance.
  • Research is exploring translational regulation of DHFR and gene transfer for resistance protection.
  • New antifolate agents targeting DHFR and TS have been developed, showing efficacy.

Conclusions:

  • Methotrexate (MTX) continues to be a potent and widely utilized chemotherapeutic agent.
  • Understanding antifolate mechanisms and resistance is vital for developing improved cancer treatments.
  • Ongoing research promises further advancements in antifolate therapy for various malignancies.

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